One main consequence of numerous cardiovascular, neurologic and respiratory disorders, whether in the neonate, older infant or at a later more mature age, is tissue O2 deprivation. Clinically, such a consequence can have devastating effects, especially on susceptible organs such as the brain, heart and kidney. Besides the type of organ, there are a number of factors that can determine the response of tissue to hypoxia. It has been well demonstrated that the developing mammal responds differently to hypoxia than the mature subject, both in vivo and in-vitro. Our overall Program hypothesis is that O2 deprivation leads to alterations in cytosolic, membrane and nuclear events that form the underlying basis for cellular adaptation, sublethal injury or cell death. The extent of these alterations depends on many factors including age, type cell and its endowments in both excitable (e.g. neurons and cardiac myocytes) and nonexcitable cells (e.g. glia, renal tubular epithelium), and severity and chronicity of hypoxia. The central aims of this Program will therefore be to 1) to define the nature of the responses to hypoxia in mature and immature neurons, glia, cardiac myocytes and epithelia and 2) to identify the mechanisms underlying these developmental changes at the cellular and molecular levels using a variety of approaches and techniques. To address these aims and determine the mechanisms that can lead to injury or adaptation and survival in the mature and immature cell, we are submitting a revised competing renewal of our Program Project. This program is based on 4 major projects that are interactive, interdependent and that share facilities (4 Cores), concepts and experimental approaches. To accomplish these aims, we use state-of-the art techniques and methodologies including eletrophysiologic methods, electron, confocal and video-microscopy, molecular biologic and genetic techniques to study native tissue, dissociated and cultured cells. The studies outlined in this Program represent a natural extension of work currently done by each PI in the Program. We firmly believe that this Program will provide the opportunity of enhancing the productivity of each individual project and, perhaps more importantly, the synthesis of new concepts about susceptibility or tolerance to anoxia and the formulation of therapeutic modalities.